Dapsone (4,4'-diaminodiphenyl sulfone, DDS) and its repository form, acedapsone (4,4'-diacetamidodiphenyl sulfone, DADDS), have emerged as the most efficacious agents for treatment of leprosy. Both DDS and DADDS (through hydrolysis to DDS) exhibit high activity and low orders of toxicity at effective doses. Recent reports of DDS-resistant disease of as high as 10% of lepromatous patients in some areas indicate the need for improvement over monotherapy. That rifampin (RFM) and clofazamine (B663) are active against DDS-resistant M. leprae suggests that combined therapy for lepromatous leprosy may reduce this problem. Certain 2,4-diminoquinazolines, show promise from experimental studies. During the past eight years of grant support, we have developed procedures for the measurement of DDS and its derivatives in plasma and urine of man and have assessed numerous species as potential models of man for DDS disposition. The minimal inhibitory concentration of DDS against M. leprae in mice and rats range from 2 to 4 ng/ml of plasma or g of tissue at sites of infection. Several studies on the levels of DDS and its derivatives in DDS-sensitive and DDS-resistant leprosy patients did not disclose any relationships between levels of drug and DDS resistance or therapeutic response. Our objectives include the development of procedures for measuring 2,4-diaminoquinazoline derivatives in biological fluids of mice; an assessment of the disposition of DDS and its derivatives in the armadillo, a recently established host for the multiplication of M. leprae; an examination of oxidative metabolism of DDS by rat liver preparations and the influence of RFM thereon; tests of the mutagenic activity of N-hydroxy DDS derivatives in a bacterial screening system followed by tests of their carcinogenic activity in rats; the development of procedures for employing saliva as a means of obtaining pharmacokinetic data on the disposition of DDS in man; and a more complete assessment of the patterns of DDS metabolites in the urine of volunteers receiving DDS prophylactically and patients receiving DDS alone and in combination with RFM therapeutically.